Project Summary/Abstract Oral cancer patients suffer from excruciating pain with severely impaired function (e.g., eating, drinking, speaking). The onset of oral cancer pain appears to coincide with the transition of pre- cancerous lesions to cancer. The mechanisms of oral cancer pain are largely unknown. Current research on cancer pain mainly focuses on the interaction between the cancer microenvironment and primary afferent neurons. By contrast, the role of Schwann cells, the most prevalent cell type supporting peripheral nerves, has not been defined in oral cancer pain. During tissue inflammation or injury, Schwann cells are activated and undergo phenotypic changes. They dedifferentiate, proliferate, migrate, and secrete pro-nociceptive mediators. Thus, Schwann cells could significantly influence the cancer microenvironment and neuronal function. Our central hypothesis is that cancer-activated Schwann cells can induce neuronal excitation and nociception by releasing pro-nociceptive mediators. This hypothesis is supported by our preliminary data showing that Schwann cells become activated in the presence of oral cancer cells and that cancer activated Schwann cells release mediators that are nociceptive when injected into mice. There is minimal activation of Schwann cells by dysplasia or non- tumorigenic cell lines. The hypothesis will be tested by identifying pro-nociceptive mediators released by cancer-activated Schwann cells (Aim 1) and by measuring the magnitude of Schwann cell activation in relation to nociception during cancer progression in a mouse carcinogenesis model (Aim 2). Schwann cells are currently not recognized as a contributor or therapeutic target for oral cancer pain. The proposed study will improve our current understanding of the cellular and molecular mechanisms of oral cancer pain, and assist in developing novel therapies for oral cancer pain control. Better pain management will improve the quality of life and survival in oral cancer patients.